Retinoid-like heterocycles

ABSTRACT

This invention relates to a compound of formula I  and Rb are independently C1-6 alkyl; Rc is C1-6 alkyl or hydrogen; and R is heteroaryl and these compounds are useful in preventing and treating skin disorders.

FIELD OF INVENTION

The present invention provides compounds having retinoid-like activity.More specifically, the compounds of the present invention are useful forpreventing and/or treating various skin disorders, such as, but notlimited to, acne, psoriasis and damage from irradiation. Further, theyhave antitumor activities.

BACKGROUND OF THE INVENTION

Retinoic acid and its natural and synthetic analogues (retinoids) exerta wide array of biological effects. ##STR2##

They have been shown to affect cellular growth and differentiation andare promising drugs for the treatment of several cancers. Roberts, A.B.and Sporn, M. B. in "The Retinoids," Sporn, M. B., Roberts, A. B., andGoodman, D. S., eds, 1984, 2, pp. 209-286, Academic Press, New York;Lippman, S. M., Kessler, J. F., and Meyskens, F. L., Cancer Treat. Rep.,1987, 71, p. 391; ibid., p. 493; Hong, W. K. et al., N. Engl. J. Med.,1990, 323, p. 795; Huang, M. et al., Blood, 1988, 72, p. 567. A fewretinoids are already in clinical use in the treatment of dermatologicaldiseases such as acne and psoriasis. For example, isotretinoin is usedclinically for oral therapy of severe ache, and etretinate isparticularly useful in the treatment of psoriasis. Orfanos, C. E.,Ehlert, R., and Gollnick, H., Drugs, 1987, 34, pp. 459-503. ##STR3##

Other examples of retinoid compounds include retinobenzoic acids offormula II and III, in which Q equals --NHCO--, --CONH--, --COCH═CH--,--CH═CHCO--, --COCH₂ --, etc. ##STR4##

See for example: Loeliger, P., Bollag, W., and Mayer, H., Eur. J. Med.Chem. 1980, 15, pp. 9-15; Kagechika, H. et al., J. Med. Chem., 1988, 31,No. 11, pp. 2182-2192.

SUMMARY OF INVENTION

The present invention relates to a compound of formula I ##STR5## or anontoxic pharmaceutically acceptable salt, physiologically hydrolyzableester or solvate thereof, in which

T is --CONH-- or --CH═CH--;

R^(a) and R^(b) are independently C₁₋₆ alkyl;

R^(c) is C₁₋₆ alkyl or hydrogen; and

R is a heteroaryl.

Also provided by this invention are methods for preventing and/ortreating tumors and non-malignant skin disorders comprisingadministering a compound of formula I to a mammal. Further provided is apharmaceutical formulation (composition) comprising a compound offormula I in admixture with (a) pharmaceutically acceptableexcipient(s).

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is the cytotoxicity dose response curves for lung line L2987.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a compound of formula I ##STR6## or anontoxic pharmaceutically acceptable salt, physiologically hydrolyzableester or solvate thereof, in which

T is --CONH-- or --CH═CH--;

R^(a) and R^(b) are independently C₁₋₆ alkyl;

R^(c) is C₁₋₆ alkyl or hydrogen; and

R is heteroaryl.

In the instant application, the numbers in subscript after the symbol"C" define the number of carbon atoms a particular group can contain.For example, C1-6alkyl refers to straight and branched chain alkylgroups with one to six carbon atoms and such groups include methyl,ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl,3-methylpentyl, or the like alkyl groups; C₃₋₆ cycloalkyl refers tocyclopropyl, cylcobutyl, cyclopentyl, or cyclohexyl; and halogen refersto fluorine, chlorine, bromine, or iodine.

Heteroaryl refers to a fully unsaturated monocylic or bicylic ringstructure with 5 or 6 atoms in each ring, and further characterized byhaving at least one heteroatom, selected from nitrogen, oxygen orsulfur, in at least one ring. For example when heteroaryl isfive-membered it contains at least one heteroatom selected from sulfur,oxygen or nitrogen, but up to 1 sulfur, 1 oxygen or 4 nitrogen atoms;when heteroaryl is a six-membered it contains from 1 to 4 nitrogenatoms. Examples of monocylic heteroaryl include thienyl, furyl,pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl,thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,triazinyl, tetrazinyl, and like rings. Examples of bicyclic heteroarylinclude indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzothiazolyl,benzoxazolyl, benzimidazolyl, benzoxadiazolyl, and benzofurazanyl.Heteroaryl can also be optionally substituted with C₁₋₆ alkyl.Heteroaryl can also be substituted with one to three C₁₋₆ alkylgroup(s). Preferred heteroaryl of this invention is a radical of theformula ##STR7## In the instant application all symbols once definedretain the same meaning until they are redefined.

Some compounds of formula I may also form pharmaceutically acceptablemetal and amine salts in which the cation does not contributesignificantly to the toxicity or biological activity of the salt. Thesesalts are also part of the present invention. Suitable metal saltsinclude the sodium, potassium, calcium, barium, zinc, and aluminumsalts. The sodium or potassium salts are preferred. Amines which arecapable of forming stable salts group include trialkylamines such astriethylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine,1-ephenamine, N,N'-dibenzylethylenediamine, dehydroabietylamine,N-ethylpiperidine, benzylamine, dicyclohexylamine, or the likepharmaceutically acceptable amines.

When compounds of formula I contains carboxy groups, it can formphysiologically hydrolyzable esters which serve as prodrugs by beinghydrolyzed in the body to yield formula I compounds per se. They arepreferably administered orally since hydrolysis in many instances occursprincipally under the influence of the digestive enzymes. Parenteraladministration may be used where the ester per se is active, or in thoseinstances where hydrolysis occurs in the blood. Examples ofphysiologically hydrolyzable esters of compounds of formula I includeC₁₋₆ alkyl, benzyl, 4-methoxybenzyl, indanyl, phthalidyl, methoxymethyl,C₁₋₆ alkanoyloxyC₁₋₆ alkyl, e.g. acetoxymethyl, pivaloyloxymethyl orpropionyloxymethyl, C₁₋₆ alkoxycarbonyloxyC₁₋₆ alkyl, e.g.methoxycarbonyloxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl,phenylglycyloxymethyl, (5-methyl-2-oxo-1-3-dioxolen-4-yl)-methyl andother well-known physiologically hydrolyzable esters used, for example,in the penicillin and cephalosporin arts. Such esters are prepared byconventional techniques known in the art.

The structural formulae as drawn in the instant application are believedto best represent the structures of compounds of the present invention.However, some compounds within the scope of the invention may exist asother tautomeric forms, in which hydrogen atoms are transposed to otherparts of the molecules and the chemical bonds between the atoms of themolecules are consequently rearranged. It should be understood that thestructural formulae represent all tautomeric forms, insofar as they mayexist.

The synthesis of a compound of formula I can be accomplished by a widevariety of methods using conventional starting materials and processes.The synthetic descriptions and specific examples that follow are onlyintended for the purpose of illustration, and are not to be construed aslimiting in any manner ways to make compounds of the present inventionby any other methods.

Typically a compound of formula I may be made by employing one of theprocesses as depicted in Schemes I to VI or obvious variations thereof.All the steps in Schemes I to VI are standard processes which can beeasily practiced by anyone skilled in the art. The specific examplesthat follow are intended to illustrate specific conditions which may beemployed to carry certain steps in the Schemes and are not to beconstrued as limiting the conditions in any way.

In the Schemes, R¹ is a carboxy protecting group preferably C₁₋₆ alkyl;and even more preferably it is methyl, ethyl or t-butyl. When R¹ ist-butyl, it can be removed by trifluoroacetic acid. In Scheme IV, R^(d)refers to an amide protecting group as represented by t-butoxycarbonylor 2-(trimethylsilyl)ethoxymethyl. ##STR8##

DESCRIPTION OF SPECIFIC EMBODIMENTS

The specific examples which follow illustrate the synthesis ofrepresentative compounds of the instant invention and are not to beconstrued as limiting the invention in sphere or scope. The methods maybe adapted to variations in order to produce compounds embraced by thisinvention but not specifically disclosed. Further, variations of themethods to produce the same compounds in somewhat different fashion willalso be evident to one skilled in the art.

All temperatures are understood to be in Centigrade (C) when notspecified. The nuclear magnetic resonance (NMR) spectral characteristicsrefer to chemical shifts (δ) expressed in parts per million (ppm) versustetramethylsilane (TMS) as reference standard. The relative areareported for the various shifts in the proton NMR spectral datacorresponds to the number of hydrogen atoms of a particular functionaltype in the molecule. The nature of the shifts as to multiplicity isreported as broad singlet (bs), broad doublet (bd), broad triplet (bt),broad quartet (bq), singlet (s), multiplet (m), doublet (d), quartet(q), triplet (t), doublet of doublet (dd), doublet of triplet (dr), anddoublet of quartet (dq). The solvents employed for taking NMR spectraare DMSO-d₆ (perdeuterodimethylsulfoxide), D₂ O (deuterated water),CDCl₃ (deuterochloroform) and other conventional deuterated solvents.The infrared (IR) spectral description include only absorption wavenumbers (cm⁻¹) having functional group identification value.

Celite is a registered trademark of the Johns-Manville ProductsCorporation for diatomaceous earth.

The abbreviations used herein are conventional abbreviations widelyemployed in the art. Some of which are:

    ______________________________________                                        MS           mass spectrometry                                                HRMS         high resolution mass spectrometry                                Ar           aryl                                                             DCI          desorption chemical ionization                                   Hex          hexane(s)                                                        tBu          tertiarybutyl                                                    h            hour(s)                                                          min          minute(s)                                                        Ph           phenyl                                                           Y            yield                                                            THF          tetrahydrofuran                                                  Tf.sub.2 O   triflic anhydride                                                             (trifluoromethanesulfonic                                                     anhydride)                                                       Pd.sub.2 dba.sub.3                                                                         tris(dibenzylidene acetone)-                                                  dipalladium (0)                                                  SEMCl        2-(trimethylsilyl)ethoxymethyl                                                chloride                                                         IS           Ion spray                                                        ______________________________________                                    

EXAMPLE 1 4,4-Dimethyl-7-diazotetrafluoroborate-1-tetralone (Va)

To 4,4-dimethyl-7-amino-1-tetralone (15.10 g, 9.89 mmol) was added 48%fluoroboric acid (28 mL) diluted with water (28 mL) at O° C. A coldsolution of sodium nitrate (13.75 g, 199 mmol) in water (28 mL) wasadded slowly while keeping the temperature at about 10° C. The mixturewas then cooled to 0° C., filtered and washed with 5% fluoboric acid(200 mL) and dried in vacuo to give 20.5 g (Y: 89%) of the titlecompound. ¹ H-NMR (DMSO-d₆): δ9.15 (d, J=2.5 Hz, 1H), 8.75 (dd, J=8.5,2.5 Hz, 1H), 8.20 (d, J=8.5 Hz, 1H), 2.87 (t, J=7.0 Hz, 2H), 2.07 (t,J=7.0 Hz, 2H), 1.43 (s, 6H); MS (DCI) m/e: 193 (MH⁺ -N₂ BF₄).

EXAMPLE 2 4,4-Dimethyl-7-hydroxy-1-tetralone (VIa)

Compound Va (1.19 g, 4.13 mmol) was added to an already boiling solutionof sulfuric acid (3 mL) and water (30 mL). After 1 hour at reflux thereaction mixture was cooled and extracted with ethyl acetate (2×50 mL).The combined organic phases were concentrated in vacuo and the residuechromatographed on silica gel (eluted with 20% ethyl acetate in hexane)to give 690mg (Y: 88%) of the title compound. ¹ H-NMR (CDCl₃): δ7.48 (d,J=2.5 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.05 (dd, J=8.5, 2.5 Hz, 1H),2.75 (t,J=7.0 Hz, 2H), 2.00 (t, J=7.0 Hz, 2H), 1.38 (s, 6H).

EXAMPLE 3 4,4-Dimethyl-7-trifluoromethanesulfonate-1-tetralone (VIIa)

To a solution of compound VIa (690 mg, 3.63 mmol) in anhydrous pyridine(10 mL) was added trifluoromethanesulfonic anhydride (4.42 mmol, 0.74mL) at 0° C. The reaction mixture was then allowed to warm to roomtemperature. After 16 hours, 1N HCl (25 mL) was added and the mixturewas extracted with ethyl acetate (2×50 mL). The combined organic phaseswere dried over anhydrous magnesium sulfate and concentrated in vacuo togive 1.17 g (Y: 100%) of the title compound. ¹ H-NMR (CDCl₃): δ7.88 (d,J=2.8 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.40 (dd, J=8.7, 2.8 Hz, 1H),2.76 (t, J=7.0 Hz, 2H), 2.04 (t, J=7.0 Hz, 2H), 1.40 (s, 6H); MS (DCI)m/e: 323 (MH⁺).

EXAMPLE 4 5,5-Dimethyl-8-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylicacid, methyl ester (VIIIa) ##STR9##

To a solution of compound VIIa (1.15 g, 3.57 mmol) in methanol (11 mL)and dimethyl sulfoxide (11 mL) was added triethylamine (1.09 mL, 7.82mmol) palladium (II) acetate (24 mg, 0.11 mmol) and1,3-bis(diphenylphosphino) propane (44 mg, 0.11 mmol). The reactionmixture was then saturated with carbon monoxide at room temperature andheated to 70° C. under a balloon of carbon monoxide for 3 hours. Aftercooling to room temperature, the reaction mixture was poured into waterand extracted with ethyl acetate. The organic phase was thenconcentrated in vacuo and the residue chromatographed on silica gel(eluted with 15% ethyl acetate in hexane) to give 692 mg (Y: 93%) of thetitle product. ¹ H-NMR (CDCl₃): δ8.66 (d, J=2.0 Hz, 1H), 8.18 (dd,J=8.3, 2.0 Hz, 1H), 7.52 (d, J=8.3 Hz, 1H), 3.92 (s, 3H), 2.76 (t, J=7.0Hz, 2H), 2.04 (t, J=7.0 Hz, 2H), 1.41 (s, 6H); MS (DCI) m/e: 233 (MH⁺) .

EXAMPLE 55,5-Dimethyl-8-hydroxy-8-(2-thienyl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylicacid,methyl ester (Xa) ##STR10##

To a solution of compound VIIIa (275 mg, 1.19 mmol) in tetrahydrofuran(5 mL) at -78° C. was added 2-thienylithium (1.0M solution intetrahydrofuran, 1.78 mmol, 1.78 mL). After warming to room temperature(2 hours), the reaction mixture was concentrated and the residuechromatographed on silica gel (eluted with 10% ethyl acetate in hexane)to give 252 mg (Y: 67%) of the title product. Title product uponisolation, was not stable and some elimination occurred. Mixture wasused as is in the following step:

EXAMPLE 65,5-Dimethyl-5,6-dihydro-8-(2-thieny1)-naphthalene-2-carboxylic acid(XIa) ##STR11##

To a solution of compound Xa (252 mg, 0.80 mmol) in toluene (10 mL) wasadded (3-6 mg) of p-toluenesulfonic acid. After heating at 70° C. for 5minutes, the reaction mixture was cooled and concentrated in vacuo. Theresidue was then dissolved in ethyl alcohol (7 mL) and treated with 10NNaOH (10.0 mmol, 1.0 mL) at room temperature. After 16 h an excess of ¹N HCl (30 mL) was added and the precipitate collected by vacuumfiltration to give 195 mg (Y: 86%) of the title product. ¹ H NMR (DMSO):δ7.86 (m, 2H), 7.55 (d, J=4.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.13 (m,2H), 6.23 (t, J=4.5 Hz, 1H), 2.33 (d, J=4.5 Hz, 2H), 2.33 (s, 6H). MS(DCI) m/e: 285 (MH⁺).

EXAMPLE 74-[[[[5,6-Dihydro-5,5-dimethyl-8-(2-thienyl)]-2-naphthalenyl]carbonyl]amino]benzoicacid, methyl ester (I¹ a) ##STR12##

A solution of compound XIa (195 mg, 0.69 mmol) in anhydrous methylenechloride (7 mL) was treated with oxalyl chloride (0.20 mL, 2.29 mmol)and 2 drops of N,N-dimethylformamide at 0° C. The reaction mixture wasthen allowed to stir at room temperature. After 2 hours, the mixture wasconcentrated in vacuo. The residue was dissolved in anhydrous pyridine(6 mL) to which was added methyl 4-aminobenzoate (Aldrich, 104 mg, 0.69mmol). After 2 hours at room temperature, the mixture was diluted with1N HCl, extracted with ethyl acetate (100 mL), washed with ¹ N HCl(3×100 mL) and washed with saturated sodium bicarbonate (2×100 mL). Theorganic phase was then separated, concentrated in vacuo and the residuechromatographed on silica gel (eluted with 20% ethyl acetate in hexane)to give 166 mg (Y: 58%) of the title product. ¹ H NMR (CDCl₃): δ8.05 (d,J=8.7 Hz, 1H), 7.88 (d, J=1.9 Hz, 1H), 7.80-7.65 (m, 6H), 7.50 (d, J=8.0Hz, 1H) , 7.10 (d, J=2.9 Hz, 1H), 6.27 (t, J=4.5 Hz, 1H), 3.91 (s, 3H),2.38 (d, J=4.5 Hz, 2H), 1.36 (s, 6H). MS (DCI) m/e: 418 (MH⁺).

EXAMPLE 84-[[[[5,6-Dihydro-5,5-dimethyl-8-(2-thienyl)]-2-naphthalenyl]carbonyl]amino]benzoicacid (I² a) ##STR13##

To a stirred solution of compound I¹ a (166 mg, 0.45 mmol) in absoluteethyl alcohol (7 mL) was added 10N NaOH (0.40 mL, 4.0 mmol) at roomtemperature. After 24 hours, an excess of ¹ N HCl (30 mL) was added. Theprecipitate was collected by vacuum filtration, washed with 1N HCl andair dried to give 131 mg (Y: 82%) of the title compound. ¹ H NMR (DMSO):δ12.76 (s, 1H) , 10.49 (s, 1H), 7.90 (m, 6H), 7.53 (m, 2H), 7.14 (m,2H), 6.26 (t, J=4.5 Hz, 1H), 2.34 (d, J=4.5 Hz, 2H) , 1.29 (s, 6H). ¹³ CNMR: 166.94, 165.99, 148.65, 143.29, 141.30, 132.66, 132.57, 131.37,130.23, 128.70, 127.64, 127.29, 125.94, 125.41, 125.14, 124.78, 124.12,119.42, 37.79, 33.42, 27.67. MS (DCI) m/e: 404 (MH⁺). IR (KBr): 2960,1688, 1594, 1520. Anal. calcd for C₂₄ H₂₁ O₃ N₁ S₁.0.25 H₂ O: C, 70.65;H, 5.31; N, 3.43. Found: C, 70.40; H, 5.24; N, 3.21.

EXAMPLE 95,5-Dimethyl-8-hydroxy-8-[2-(3-methylthienyl)]-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid, methyl ester (Xb) ##STR14##

To a solution of compound VIIIa (200 mg, 0.86 mmol) in tetrahydrofuran(4 mL) at -5° C. was added 3-methyl-2-thienyllithium [0.25M solution inTHF, 1.29 mmol, 5.17 mL; prepared by treating 3-methyl-2-bromothiophene(909 mg, 5.13 mmol) in tetrahydrofuran (18.4 mL) with n-butyllithium(2.5N solution in hexanes, 5.375 mmol, 2.15 mL) at -78° C. After 5minutes at -78° C., 5.17 mL was transferred via syringe to the solutionof compound VIIIa. After warming to room temperature, the reactionmixture was concentrated and the residue chromotographed on silica gel(eluted with 10% ethyl acetate in hexane) to give 70 mg (Y: 25%) of thetitle compound. ¹ H NMR (CDCl₃): δ7.95 (m, 2H), 7.47 (d, J=9.0 Hz, 1H),7.10 (d, J=5.0 Hz, 1H), 6.80 (d, J=5.0 Hz, 1H), 3.85 (s, 3H), 2.40 (m,1H), 2.10 (m, 2H), 1.82 (s, 3H), 1.65 (m, 1H), 1.45 (s, 3H), 1.35 (s,3H). MS (DCI)m/e: 331 (MH⁺).

EXAMPLE 105,5-Dimethyl-5,6-dihydro-8-[2-(3-methylthienyl)]-naphthalene-2-carboxylicacid (XIb) ##STR15##

Using the method given for the preparation of the 8-(2-thienyl)derivative XIa, 240 mg (0.73 mmol) of compound Xb gave 209 mg (Y: 92%)of the title product. ¹ H NMR (CDCl₃): δ7.93 (d, J=8.0 Hz, 1H), 7.64 (s,1H), 7.42 (d, J=8.0 Hz, 1H), 7.19 (d, J=5.0 Hz, 1H), 6.90 (d, J=5.3 Hz,1H), 6.13 (t, J=4.5 Hz, 1H), 2.39 (d, J=4.5 Hz, 2H), 2.01 (s, 3H), 1.36(s, 6H). MS (DCI) m/e: 299 (MH⁺) .

EXAMPLE 114-[[[[5,6-Dihydro-5,5-dimethyl-8-[2-(3-methylthienyl)]]-2-naphthalenyl]carbonyl]amino]benzoicacid methyl ester (I¹ b) ##STR16##

Using the method given for the preparation of the 8-(2-thienyl)derivative I¹ a, 195 mg (0.65 mmol) of compound XIb gave 220 mg (Y: 78%)of the title product. ¹ H NMR (CDCl₃): δ8.03 (d, J=8.7 Hz, 2H) , 7.70(s, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.67 (d, J=8.7 Hz, H), 7.48 (d, J=8.0Hz, 1H), 7.43 (d, J=2.0 Hz, 1H) , 7.22 (d, J=5.0 Hz, 1H), 6.92 (d, J=5.0Hz, 1H), 6.17 (t, J=4.5 Hz, 1H), 3.91 (s, 3H), 2.41 (d, J=4.5 Hz, 2H),2.05 (s, 3H), 1.38 (s, 6H). MS (DCI) m/e: 432 (MH⁺) .

EXAMPLE 124-[[[[5,6-Dihydro-5,5-dimethyl-8-[2-(3-methylthienyl)]]-2-naphthalenyl]carbonyl]amino]benzoicacid (I² b) ##STR17##

Using the method given for the preparation of the 8-(2-thienyl)derivative I² a, 220 mg (0.74 mmol) of compound I¹ b gave 50 mg (Y: 24%)of the title product. ¹ H NMR (DMSO): δ12.73 (s, 1H), 10.45 (s, 1H),7.87 (m, 5H), 7.53 (d, J=8.0 Hz, 1H), 7.45 (d, J=5.0 Hz, 1H), 7.35 (d,J=1.9 Hz, 1H), 6.98 (d, J=5.0 Hz, 1H), 6.15 (t, J=4.5 Hz, 1H), 2.38 (d,J=4.5 Hz, 2H), 1.96 (s, 3H), 1.33 (s, 6H). MS (DCI)m/e: 418 (MH⁺). HRMSDeviation 2.2 ppM. Calc. 418. 1477. Found: 418.1468. IR (KBr): 2960,1688, 1594, 1520.

EXAMPLE 135,5-Dimethyl-8-hydroxy-8-(5-pyrimidinyl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylicacid, methyl ester (Xc) ##STR18##

Using the method given for the preparation of the8-[2-(3-methylthienyl)]derivative Xb, reaction at -78° C. of compoundVIIIa (535 mg, 2.31 mmol) and 5-pyrimidinyl lithium (0.29M solution inTHF, 2.88 mmol, 10.0 ml; prepared by treating 5-bromopyrimidine in THFwith n-butyllithium at -78° C.) gave 84 mg (Y: 12%) of the titlecompound. Title product upon isolation was not stable and someelimination occurred. Mixture was used as is in the following step.

EXAMPLE 145,5-Dimethyl-5,6-dihydro-8-(5-pyrimidinyl)-naphthalene-2-carboxylic acid(XIc) ##STR19##

Using the method given for the preparation of the 8-(2-thienyl)derivative XIa, 167 mg (0.535 mmol) of compound Xc gave 140 mg (Y: 93%)of the title product. ¹ H NMR (DMSO): δ9.23 (s, 1H), 8.82 (s, 2H), 7.87(dd, J=8.0, 1.7 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.38 (d, J=1.6 Hz, 1H), 6.28 (t, J=4.5 Hz, 1H ), 2.41 (d, J=4.5 Hz, 2H), 1.32 (s, 6H). MS(DCI)m/e: 281 (MH⁺).

EXAMPLE 154-[[[[5,6-Dihydro-5,5-dimethyl-8-(5-pyrimidinyl)]-2-naphthalenyl]carbonyl]amino]benzoicacid, methyl ester (I¹ C) ##STR20##

Using the method given for the preparation of the 8-(2-thienyl)derivative I¹ a, 140 mg (0.50 mmol) of compound XIc gave 60 mg (Y: 29%)of the title product. ¹ H NMR (CDCl₃): δ8.17 (d, J=8.6 Hz, 1H), 8.03 (d,J=8.4 Hz, 2H), 7.76 (d, J=8.5 Hz, 1H), 7.67 (m, 3H), 7.54 (d, J=8.0 Hz,1H), 7.40 (s, 1H), 6.19 (t, J=4.5 Hz, 1H), 3.90 (s, 3H), 2.47 (d, J=4.5Hz, 2H), 1.39 (s, 6H). MS (DCI)m/e: 414 (MH⁺).

EXAMPLE 164-[[[[5,6-Dihydro-5,5-dimethyl-8-(5-pyrimidinyl)]-2-naphthalenyl]carbonyl]amino]benzoicacid (I² c) ##STR21##

Using the method given for the preparation of the 8-(2-thienyl)derivative I² a, 60 mg (0.15 mmol) of compound I¹ c gave 16 mg (Y: 28%)of the title product. ¹ H NMR (DMSO): δ10.45 (s, 1H), 9.22 (s, 1H), 8.84(s, 2H), 7.93-7.80 (m, 5H), 7.59 (d, J=8.1 Hz, 1H), 7.39 (d, J=1.7 Hz,1H ), 6.30 (t, J=4.5 Hz, 1H ), 2.42 (d, J=4.5 Hz, 2H), 1.34 (s, 6H). MS(DCI)m/e: 400 (MH⁺). HRMS Deviation 3.1 ppM. Calcd: 400.1661. Found:400.1649. IR (KBr): 2960, 1684, 1596, 1526.

EXAMPLE 17 N-(2-Pyridyl)triflimide ##STR22##

The title compound was prepared by procedure of Comins & Dehghani,Tetrahedron Lett., Vol. 33, No. 42, 1992, p. 6299. ¹ H NMR (CDCl₃):δ8.66 (m, 1H), 7.95 (m, 1H), 7.56 (m, 1H), 7.48 (d, 1H). MS (DCI)m/e:359 (MH⁺).

EXAMPLE 185,5-Dimethyl-5,6-dihydro-8-(trifluoro-methanesulfonyloxy)-naphthalene-2-carboxylicacid, methyl ester (XIIa) ##STR23##

To a solution of compound VIIIa (606 mg, 2.61 mmol) in tetrahydrofuran(15 mL) at -78° C. was added lithium bis (trimethylsilyl ) amide (1.0Msolution in hexane, 2.87 mmo 1, 2.87 mL ) and thenN-(2-pyridyl)triflimide (2.87 mmol, 1.03 g) at -78° C. Reaction mixturewas stirred at -78° C. for 0.5 h and then warmed to room temperature.The mixture was diluted with water and extracted with ethyl acetate(2×50 mL). The organic phases were combined and concentrated in vacuo.The residue was chromatographed on silica gel (eluted with 5% ethylacetate in hexane) to give 844 mg (Y: 89%) of the title product. ¹ H NMR(CDCl₃): δ8.05 (m, 2H), 7.40 (d, J=8.0 Hz, 1H) , 6.05 (t, J=4.5 Hz, 1H),3.92 (s, 3H), 2.46 (d, 4.5 Hz, 2H), 1.33 (s, 6H) .

EXAMPLE 19 3-Tributlstannylfuran ##STR24##

A solution of 3-bromofuran (Aldrich, 300 g, 20.4 mmol) in anhydroustoluene (50 mL) was treated with bis(tributyltin) (Aldrich, 27.8 g, 47.9mmol) and tetrakis(triphenylphosphine)palladium (0) (Aldrich, 0.20 mmol,236 mg). The reaction mixture was allowed to reflux for 16 hours. Themixture was then concentrated in vacuo and the residue waschromatographed on C-18 (eluted with 100% methylene chloride) to give3.31 g (Y: 50%) of the title product. ¹ H NMR (CDCl₃): δ7.57 (s, 1H),7.25 (d, J=6.0 Hz, 1H), 6.36 (s, 1H), 1.52 (m, 6H), 1.31 (m, 6H), 1.00(t, J=8.2 Hz, 6H) , 0.92 (t, J=7.4 Hz, 9H). MS (DCI) m/e: 359 (MH⁺).

EXAMPLE 20 5,5-Dimethyl-5,6-dihydro-8-(3-furyl)-naphthalene-2-carboxylicacid, methyl ester (XIIIa) ##STR25##

A solution of compound XIIa (309 mg, 0.85 mmol) in anhydrous1-methyl-2-pyrrolidinone (4 mL) was treated with triphenylarsine (49 mg,0.16 mmol) and tris(dibenzylidene acetone)-dipalladium (0) (24 mg, 0.026mmol) at room temperature. After 5 minutes, 3-tributylstannylfuran (610mg, 1.87 mmol) in anhydrous 1-methyl-2-pyrrolidinone (1 mL) was added tothe reaction mixture. After 1 hour at room temperature, the mixture wasdiluted with water and extracted with ethyl acetate (2×50 mL). Theorganic phases were combined and concentrated in vacuo. The residue waschromatographed on silica gel (eluted with 10% ethyl acetate in hexane)to give 240 mg (Y: 99%) of the title product. ¹ H NMR (CDCl₃): d 7.97(s, 1H), 7.91 (dd, J=8.0, 1.8 Hz, 1H), 7.54 (s, 1H), 7.49 (d,J=1.8 Hz,1H), 7.42 (d, J=8.0 Hz, 1H), 6.50 (s, 1H), 6.10 (t, J=4.5 Hz, 1H), 3.87(s, 3H), 2.32 (d, J=4.5 Hz, 2H), 1.33 (s, 6H). MS (DCI) m/e: 283 (MH⁺).

EXAMPLE 21 5,5-Dimethyl-5,6-dihydro-8-(3-furyl)-naphthalene-2-carboxylic acid (XId) ##STR26##

To a stirred solution of compound XIIIa (0.75 mmol, 210 mg) in ethanol(5 mL) was added 10N NaOH (0.75 mL, 7.5 mmol) at room temperature. After3 hours, an excess of 1N HCl (30 mL) was added. The precipitate wascollected by vacuum filtration, washed with 1N HCl and air dried to give175 mg (Y: 88%) of the title compound. ¹ H NMR (DMSO): δ7.84 (s, 1H),7.81 (s, 2H), 7.76 (d, J=1.5 Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 6.61 (s,1H), 6.15 (t, J=4.5 Hz, 1H), 2.30 (d,J=4.5 Hz, 2H), 1.27 (s, 6H). MS(DCI)m/e 269 (MH⁺).

EXAMPLE 224-[[[[5,6-Dihydro-5,5-dimethyl-8-(3-furyl)]-2-naphthalenyl]carbonyl]amino]benzoicacid, methyl ester (I¹ d) ##STR27##

Using the method given for the preparation of the 8-(2-thienyl)derivative I¹ a, 175 mg (0.653 mmol) of compound XId gave 140 mg (Y:53%) of the title product. ¹ H NMR (CDCl₃ ): δ8.05 (d, J=8.7 Hz, 2H),7.75 (m, 4H), 7.56 (s, 1H), 7.49 (d, J=8.3 Hz, 2H), 6.51 (s, 1H), 6.15(t, J=4.5 Hz, 1H), 3.91, (s, 3H), 2.35 (t, J=4.5 Hz, 2H), 1.35 (s, 6H).MS (DCI) m/e: 402 (MH⁺).

EXAMPLE 23 4-[[[[5,6-Dihydro-5,5-dimethyl-8-(3-furyl)]-2-naphthalenyl]carbonyl]amino]benzoic acid (I² d) ##STR28##

Using the method given for the preparation of the 8-(2-thienyl)derivative I² a, 140 mg (0.35 mmol) of compound I¹ d gave 114 mg (Y:84%) of the title product. ¹ H NMR (DMSO): δ12.76 (s, 1H), 10.48 (s,1H), 7.95-7.75 (m, 8H), 7.52 (d, J=8.0 Hz, 1H), 6.66 (d, J=1.8 Hz, 1H),6.18 (t, J=4.5 Hz, 1H), 2.29 (d, J=4.5 Hz, 2H), 1.28 (s, 6H). MS(DCI)m/e: 338 (MH⁺). IR (KBr): 2960, 1688, 1594, 1522. Anal. calcd. forC₂₄ H₂₁ N₁ O₄.0.350 H₂ O: C, 73.21; H, 5.56; N, 3.56. Found: C, 73.00;H, 5.43; N, 3.35.

EXAMPLE 24 3-Tributylstannylthiophene ##STR29##

Using the method for the preparation of 3-tributylstannylfuran, 2.50 g(15.39 mmoles) of 3-bromothiophene gave 1.31 g (Y: 23%) of the titleproduct. ¹ H NMR (CDCl₃): δ7.46 (m, 1H), 7.34 (d, J=2.3 Hz, 1H), 7.16(d, J=4.6 Hz, 1H), 1.52 (m, 6H), 0.132 (m, 6H), 1.05 (t, J=8.2 Hz, 6H),0.89 (t, J=7.2 Hz, 9H). MS (DCI)m/e: 375 (MH⁺).

EXAMPLE 25 4-[[[(5,6,7,8-Tetrahydro-5,5-dimethyl-8-oxo)-2-naphthalenyl]carbonyl]amino]benzoic acid, methyl ester (XVIa)##STR30##

Using the method given for the preparation of the 8-(2-thienyl)derivative I¹ a, 1.68 g (7.71 mmol) of compound XVa (compound of formulaXV in which R^(a) and R^(b) are methyl) gave 2.10 g (Y: 78%) of thetitle product. ¹ H NMR (CDCl₃): δ8.43 (d, J=2.1 Hz, 1H), 8.21 (dd,J=8.4, 2.1 Hz, 1H), 8.07 (d, J=8.7 Hz, 2H), 7.79 (d, J=8.7 Hz, 2H), 7.61(d, J=8.4 Hz, 1H), 3.92 (s, 3H) , 2.79 (t, J=6.5 Hz, 2H), 2.07 (t, J=6.5Hz, 2H), 1.43 (s, 6H) . MS (DCI) m/e: 352 (MH⁺).

EXAMPLE 264-[[[[5,6-Dihydro-5,5-dimethyl-8-(trifluoro-methanesulfonyloxy)]-2-napthalenyl]carbonyl]amino]benzoicacid, methyl ester (XXa) ##STR31##

To a solution of compound XVIa (735 mg, 2.09 mmol) in tetrahydrofuran(10 mL) at -78° C. was added lithium diisopropylamide (1.0M solution intetrahydrofuran, 4.61 mmol, 4.61 mL) and then N- (2-pyridyl)triflimide(2.30 mmol, 824 mg) at -78° C. Reaction mixture was stirred at -78° C.for 0.5 h and then warmed to room temperature. The reaction mixture wasconcentrated in vacuo and the residue chromatographed on silica gel(eluted with 10% ethyl acetate in hexane) to give 560 mg (Y: 55%) of thetitle product. ¹ H NMR (CDCl₃): δ8.07 (d, J=8.7 Hz, 3H), 7.87 (m, 3H),7.75 (d, J=8.7 Hz, 2H), 7.48 (d, J=8.0 Hz, 1H), 6.08 (t, J=4.5 Hz, 1H),3.92 (s, 3H), 2.48 (d, J=4.5 Hz, 2H), 1.36 (s, 6H). MS (DCI) m/e 484(MH⁺) .

EXAMPLE 274-[[[[5,6-Dihydro-5,5-dimethyl-8-(3-thienyl)]-2-naphthalenyl]carbonyl]amino]benzoicacid, methyl ester (I¹ e) ##STR32##

To a solution of compound XXa (125 mg, 0.26 mmol) in1-methyl-2-pyrrolidinone (5 mL) at room temperature was addedtriphenylarsine (15 mg, 0.05 mmol), tris (dibenzylideneacetone)dipalladium (0) (7.4 mg, 0.008 mmol) and 3-tributylstannylthiophene (212mg, 0.57 mmol) in 1-methyl-2-pyrrolidinone (1 mL). After 24 hours, water(20 mL ) and ethyl acetate (20 mL ) were added. The organic phase wasseparated and stirred over an aqueous saturated potassium fluoridesolution for 30 minutes. The organic phase was again separated,concentrated in vacuo and the residue chromatographed on silica gel(eluted with 20% ethyl acetate in hexane) to give 78 mg (Y: 72%) of thetitle product. ¹ H NMR (CDCl₃): δ8.03 (d, J=8.6 Hz, 2H), 7.79 (s, 1H),7.74 (dd, J=7.9, 1.8 Hz, 1H), 7.67 (d, J=8.7 Hz, 2H), 7.49 (d, J=7.9 Hz,1H), 7.39 (m, 1H), 7.28 (m, 1H), 7.13 (d, J=4.8 Hz, 1H), 6.17 (t, J=4.5Hz, 1H), 3.91 (s, 3H), 2.37 (d, J=4.5 Hz, 2H), 1.36 (s, 6H). MS(DCI)m/e: 418 (MH⁺).

EXAMPLE 284-[[[[5,6-Dihydro-5,5-dimethyl-8-(3-thienyl)]-2-naphthalenyl]carbonyl]amino]benzoicacid (I² e). ##STR33##

Using the method given for the preparation of the 8-(2-thienyl)derivative I² a, 78 mg (0.18 mmol) of compound I¹ e gave 46 mg (Y: 61%)of the title product. ¹ H NMR (DMSO): δ12.72 (s, 1H), 10.44 (s, 1H),7.85 (m, 5H), 7.62 (m, 2H), 7.52 (m, 2H), 7.16 (dd, J=5.0, 1.3 Hz, 1H) ,6.18 (t, J=4.5 Hz, 1H), 2.33 (d, J=4.5 Hz, 2H), 1.30 (s, 6H). MS (DCI)m/e: 404 (MH⁺). IR (KBr): 2960, 1688, 1594, 1520. Anal. calcd. for C₂₄H₂₁ O₃ N₁ S₁.0.5 H₂ O: C, 69.88; H, 5.38; N, 3.40. Found: C, 69.96, H,5.05, N, 3.29.

EXAMPLE 29N-[2-(Trimethylsilyl)ethoxymethyl]-4-[[[(5,6,7,8-tetrahydro-5,5-dimethyl-8-oxo)-2-naphthalenyl]carbonyl]amino]benzoicacid, methyl ester (XVIIa) ##STR34##

A solution of compound XVIa (3.45 g, 9.83 mmol) in anhydrousN,N-dimethylformamide (40 mL) at 0° C. was treated with 60% sodiumhydride (433 mg, 10.8 mmol). When hydrogen evolution ceased2-(trimethylsilyl)ethoxymethyl chloride (2.45 g, 14.73 mmol) was slowlyadded. After 16 h at room temperature, the mixture was diluted with a10% sodium bicarbonate solution (100 mL) and extracted with diethylether. The organic phase was concentrated in vacuo and the residuechromatographed (eluted with 20% ethyl acetate in hexane) on silica gelto give 2.65 g (Y: 56%) of the title product. ¹ H NMR (CDCl₃): δ8.02 (d,J=2.0 Hz, 1H), 7.92 (d, J=8.7 Hz, 2H), 7.54 (dd, J=8.2, 2.0 Hz, 1H),7.31 (d, J=8.2 Hz, 1H), 7.23 (d, J=8.7 Hz, 2H), 5.28 (s, 2H), 3.89 (s,3H), 3.69 (m, 2H), 2.67 (t, J=7.0 Hz, 2H), 1.97 (t, J=7.0 Hz, 2H), 1.35(s, 6H), 0.97 (m, 2H), 0.00 (s, 9H). MS (DCI) m/e: 364 (M⁺ - OCH₂ CH₂ Si(CH₃)₃).

EXAMPLE 30N-[2-(Trimethylsilyl)ethoxymethyl]-4-[[[[5,6,7,8-tetrahydro-5,5-dimethyl-8-(3-pyridinyl)-8-hydroxy]-2-naphthalenyl]amino]carbonyl]benzoicacid, methyl ester (XVIIIa) ##STR35##

Using the method given for the preparation of the 8-(5-pyrimidinyl)derivative Xc, reaction of compound XVIIa (1.86 g, 3.87 mmol) and3-pyridinyl lithium (0.32M solution in THF, 8.0 mmol, 25.0 ml; preparedby treating 3-bromopyridine in THF with n-butyllithium at -78° C.) gave1.06 g (Y: 49%) of the title product. ¹ H NMR (CDCl₃): δ8.42 (dd, J=4.7,1.6 Hz, 1H) , 8.27 (dd, J=2.4, 0.8 Hz, 1H), 7.81 (d, J=8.8 Hz, 2H), 7.46(dd, J=8.2, 2.0 Hz, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.28 (m, 1H), 7.10 (m,1H), 7.05 (d, J=8.8 Hz, 2H), 7.00 (d, J=1.8 Hz, 1H), 5.23 (m, 2H), 3.94(s, 3H), 3.63 (m, 2H), 2.06 (m, 2H), 1.78 (m, 1H), 1.48 (m, 1H), 1.32(s, 3H), 1.29 (s, 3H), 0.91 (m, 2H), 0.03 (s, 9H). MS (DCI) m/e: 431(MH⁺).

EXAMPLE 314-[[[[5,6,7,8-Tetrahydro-5,5-dimethyl-8-(3-pyridinyl)-8-hydroxy]-2-naphthalenyl]amino]carbonyl]benzoicacid, methyl ester (XIXa) ##STR36##

To a solution of compound XVIIIa (865 mg, 1.54 mmol) in absolute ethanol(15 mL) was added 1N hydrochloric acid (15 mL). The reaction mixture wasstirred at 65° C. for 16 h and then cooled to room temperature. Asaturated sodium bicarbonate solution was added and the mixture was thenextracted with ethyl acetate (3×50 mL). The organic phases were thencombined, concentrated in vacuo and the residue chromatographed onsilica gel (eluted with 10% methyl alcohol in methylene chloride) togive 528 mg (Y: 80%) of the title product. ¹ H NMR (CDCl₃): δ8.47 (dd,J=4.1, 2.0 Hz, 1H), 8.41 (d, J=2.0 Hz, 1H), 8.25 (bs, 1H), 8.01 (d,J=8.7 Hz, 2H), 7.83 (dd, J=8.3, 2.0 Hz, 1H), 7.66 (d, J=8.7 Hz, 2H),7.66 (s, 1H), 7.60 (m, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.25 (m, 1H), 3.90(s, 3H), 2.22 (m, 2H), 1.87 (m, 1H), 1.60 (m, 1H). 1.41 (s, 3H), 1.38(s, 3H). MS (DCI)m/e: 431 (MH⁺).

EXAMPLE 32 4-[[[[5,6-Dihydro-5,5-dimethyl-8-(3-pyridinyl)]-2-naphthalenyl]carbonyl]amino]benzoic acid, methyl ester(I¹ f ) ##STR37##

To a solution of compound XIXa (528 mg, 1.23 mmol) in toluene (12 mL)was added p-toluenesulfonic acid monohydrate (500 mg, 2.63 mmol). Afterheating at 90° C. for 2.5 h, the reaction mixture was concentrated invacuo. The residue was diluted with saturated sodium bicarbonate (30 mL)and extracted with ethyl acetate (3×50 mL). The organic phases werecombined, concentrated in vacuo and the residue chromatographed onsilica gel (eluted with 10% methyl alcohol in methylene chloride) togive 390 mg (Y: 77%) of the title product. ¹ H NMR (CDCl₃): 6 8.61 (m,2H), 8.02 (d, J=8.7 Hz, 2H), 7.83 (s, 1H), 7.73 (dd, J=8.1, 1.0 Hz, 1H),8.55 (d, J=8.7 Hz, 2H), 8.55 (m, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.49 (d,J=l.9 Hz, 1H), 7.35 (m, 1H), 6.13 (t, J=4.5 Hz, 1H), 3.90 (s 3H), 2.43(d, J=4.5 Hz, 2H), 1.39 (s, 6H). MS (DCI)m/e: 413 (MH⁺).

EXAMPLE 334-[[[[5,6-Dihydro-5,5-dimethyl-8-(3-pyridinyl)]-2-naphthalenyl]carbonyl]amino]benzoicacid (I² f) ##STR38##

To a stirred solution of compound I¹ f (1.09 g, 2.64 mmol) in a 1:1ethanol and tetrahydrofuran solution (10 mL) was added 10 N NaOH (27.0mmol, 2.7 mL) at room temperature. After 24 hours, the reaction mixturewas made neutral by the addition of 1N HCl and then concentrated invacuo. The residue was then diluted with diethyl ether (heterogeneousmixture) and made acidic by the addition of gaseous HCl. Afteracidifying, the mixture was concentrated in vacuo and the residuechromatographed on C-18 silica gel (eluted salts with 100% water andproduct with 100% methanol) to give 540 mg (Y: 52%) of the titleproduct. ¹ H NMR (DMSO): δ12.71 (bs, 1H), 10.43 (s, 1H), 8.58 (m, 2H),7.80 (m, 6H), 7.56 (d, J=8.1Hz, 1H), 7.46 (m, 1H), 7.38 (d, J=l.6 Hz,1H), 6.18 (t, J=4.5 Hz, 1H), 2.38 (d, J=4.5Hz, 1H), 1.33 (s, 6H). MS(FAB) m/e: 399 (MH⁺). IR (KBR): 3422, 2918, 1682, 1598. Anal. calcd. forC₂₅ H₂₂ N₂ O₃.1.2 H₂ O: C, 71.33; H, 5.87; N, 6.65. Found: C, 71.03; H,5.74; N, 6.35.

EXAMPLE 34 1-Methyl-2-(tributylstannyl)pyrrole ##STR39##

Prepared according to literature method of Bailey (Tetrahedron Lett.,1986, 27, 4407-10).

EXAMPLE 354-[[[[5,6-Dihydro-5,5-dimethyl-8-(2-N-methylpyrrolyl)]-2-naphthalenyl]carbonyl]amino]benzoicacid, methyl ester (I¹ g) ##STR40##

Using the method for the preparation of compound I¹ e 120 mg of compoundXXa (0.248 mmol) gave 60 mg (Y: 58%) of the title product. ¹ H NMR(CDCl₃): δ8.03 (d, J=8.7 Hz, 2H), 7.78 (s, 1H), 7.74 (dd, J=8.2, 2.0 Hz,1H), 7.67 (d, J=8.7 Hz, 2H), 7.48 (d, J=8.0 Hz, 1H), 6.70 (t, J=2.2 Hz,1H), 6.19 (t, J=4.5 Hz, 1H), 6.15 (m, 2H), 3.91 (s, 3H), 3.39 (s, 3H),2.40 (d, J=4.5 Hz, 2H), 1.38 (s, 6H). MS (DCI)m/e: 415 (MH⁺).

EXAMPLE 364-[[[[5,6-Dihydro-5,5-dimethyl-8-(2-N-methylpyrrolyl)]-2-naphthalenyl]carbonyl]amino]benzoicacid (I² g) ##STR41##

Using the method given for the preparation of the 8-(2-thienyl)derivative I² a, 60 mg of compound I¹ g (0.145 mmol) gave 30 mg (Y: 52%)of the title product. ¹ H NMR (DMSO): δ10.45 (s, 1H), 7.84 (m, 5H), 7.52(d, J=8.1 Hz, 1H), 7.24 (d, J=1.9 Hz, 1H), 6.80 (t, J=2.2 Hz, 1H), 6.05(m, 3H), 3.33 (s 3H), 2.35 (d, J=4.5 Hz, 2H), 1.33 (s, 6H). MS (DCI)m/e: 401 (MH⁺). IR (KBr) 2960, 1688, 1596, 1522, 1410. Anal. calcd. forC₂₅ H₂₄ N₂ O₃.0.5 H₂ O: C, 73.33; H, 6.15; N, 6.84. Found: C, 73.06; H,6.02, N, 6.62.

EXAMPLE 374-[[[(5,6,7,8-Tetrahydro-5,5-dimethyl-8-oxo-2-naphthalenyl]carbonyl]N-tert-butoxycarbonyl-amino]benzoicacid, methyl ester (XVIIb) ##STR42##

A solution of compound XVIa (4.66 g, 13.28 mmol)in anhydrousacetonitrile (22 mL) at room temperature was treated with4-dimethylaminopyridine (200 mg, 1.62 mmol) followed by a solution ofdi-tert-butyldicarbonate (3.50 g, 15.0 mmol) in anhydrous acetonitrile(7 mL) in one portion with rapid stirring. After 16 h at roomtemperature, the mixture was concentrated in vacuo and the residuechromatographed (eluted with 20% ethyl acetate in hexane) on silica gelto give 4.29 g (Y: 72%) of the title product. ¹ H NMR (CDCl₃): δ8.34 (d,J=2.0 Hz, 1H), 8.11 (d, J=8.7 Hz, 2H), 7.90 (dd, J=8.0, 2.0 Hz, 1H),7.53 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.7 Hz, 2H), 3.93 (s, 3H), 2.77 (t,J=6.8 Hz, 2H), 2.08 (t, J=6.8 Hz, 2H), 1.43 (s, 6H), 1.26 (s, 9H). MS(DCI) m/e: 452 (MH⁺).

EXAMPLE 384-[[[[5,6,7,8-Tetrahydro-5,5-dimethyl-8-(4-pyridinyl)-8-hydroxy]-2-napthalenyl]carbonyl]N-tert-butoxycarbonylamino]benzoicacid, methyl ester (XVIIIb) ##STR43##

Using the method given for the preparation of the 8-(5-pyrimidinyl)derivative Xc, reaction of compound XVIII (1.01 g, 2.24 mmol) and4-pyridinyl lithium (0.32M solution in THF, 3.4 mmol, 10.5 ml; preparedby treating 4-bromopyridine in THF with n-butyllithium at -78° C.) gave168 mg (Y: 14%) of the title product. ¹ H NMR (CDCl₃): δ8.55 (d, J=6.3Hz, 2H), 8.03 (d, J=8.4 Hz, 2H), 7.69 (dd, J=8.3, 2.0 Hz, 1H), 7.52 (d,J=8.3 Hz, 1H), 7.38 (d, J=6.3 Hz, 2H), 7.33 (d, J=2.0 Hz, 1H ) , 7.18(d, J=8.4 Hz, 2H), 3.93 (s, 3H), 2.20-2.13 (m, 2H), 1.98-1.89 (m, 1H),1.67-1.58 (m, 1H), 1.42 (s, 3H) , 1.38 (s, 3H), 1.24 (s, 9H). MS (IS)m/e: 531 (MH⁺).

EXAMPLE 394-[[[[5,6,7,8-Tetrahydro-5,5-dimethyl-8-(4-pyridinyl)-8-hydroxyl-2-naphthalenyl]carbonyl]amino]benzoicacid, methy ester (XIXb) ##STR44##

To a solution of compound XVIIIb (160 mg, 0.30 mmol) in methylenechloride (5 mL) was added a 90% solution of trifluoroacetic acid inmethylene chloride (0.60 mL) at room temperature. After 1/2 h thereaction mixture was concentrated in vacuo to give 150 mg (Y: 99%) ofthe title product. ¹ H NMR (CDCl₃): δ9.04 (s, 1H), 8.53 (d, J=6.3 Hz,2H), 7.84-7.68 (m, 5H) , 7.57 (d, J=8.9 Hz, 2H), 7.53 (d, J=8.4 Hz, 1H),7.46 (d, J=l.6 Hz, 1H), 3.84 (s, 3H), 2.22-1.96 (m, 3H) , 1.62-1.54 (m,1H), 1.38 (s, 3H), 1.34 (s, 3H). MS (IS) m/e: 431 (MH⁺).

EXAMPLE 404-[[[[5,6-Dihydro-5,5-dimethyl-8-(4-pyridinyl)]-2-naphthalenyl]carbonyl]amino]benzoicacid, methyl ester ##STR45##

Using the method given for the preparation of the 8-(3-pyridinyl)derivative I¹ f, 150 mg (0.35 mmol) of compound XIXb gave 82 mg (Y: 60%)of the title product. ¹ H NMR (CDCl₃): δ8.61 (d, J=6.2 Hz, 2H), 8.06(bs, 1H), 8.01 (d, J=8.8 Hz, 2H), 7.78 (dd, J=8.1 Hz, 1H), 7.67 (d,J=8.8 Hz, 2H), 7.52-7.50 (m, 2H), 7.32 (d, J=6.2 Hz, 2H), 6.21 (t, J=4.5Hz, 1H), 3.89 (s, 3H), 2.42 (d, J=4.5 Hz, 2H), 1.37 (s, 6H). MS (IS)m/e: 413 (MH⁺).

EXAMPLE 414-[[[[5,6-Dihydro-5,5-dimethyl-8-(4-pyridinyl)]-2-naphthalenyl]carbonyl]amino]benzoic acid (I² h) ##STR46##

Using the method given for the preparation of the 8-(2-thienyl)derivative I² a, 82 mg (0.20 mmol) of compound I¹ h gave 30 mg (Y: 38% )of the title product. ¹ H NMR (DMSO): δ10.43 (s, 1H), 8.71 (d, J=6.2 Hz,2H), 7.90 (d, J=8.2, 1.6 Hz, 1H), 7.88 (d, J=8.8 Hz, 2H), 7.81 (d, J=8.8Hz, 2H), 7.61 (d, J=6.2 Hz, 2H), 7.58 (d, J=8.2 Hz, 1H), 7.44 (d, J=1.6Hz, 1H), 6.38(t, J=4.5 Hz, 1H ) , 2.41 (d, J=4.5 Hz, 2H), 1.31 (s, 6H).MS (IS) m/e: 399 (MH⁺). HRMS calculated: 399. 1709. Found: 399.1706. 0.6ppM deviation. IR (KBr): 3440, 2960, 1670, 1602.

EXAMPLE 424-[[[[5,6,7,8-Tetrahydro-5,5-dimethyl-8-[1-(2-trimethylsilanyl-ethoxymethyl)-2-imadazolyl]-8-hydroxyl-2-naphthalenyl]carbonyl]N-tert-butoxycarbonylamino]benzoic acid, methyl ester ##STR47##

Using the method given for the preparation of the 8-(5-pyrimidinyl)derivative Xc, reaction of compound XVIIb (1.25 g, 2.76 mmol) and1-(2-trimethylsilanyl-ethoxymethyl)-2-imidazoyl lithium (0.30M solutionin THF, 3.9 mmol, 13.0 ml; prepared by treating the protected imidazolewith n-butyllithium at -78° C.) gave 560 mg (Y: 31%) of the titleproduct. ¹ H NMR (CDCl₃): δ8.01 (d, J=8.75 Hz, 2H) , 7.67 (dd, J=8.2,1.9 Hz, 1H) , 7.49 (d, J=8.2 Hz, 1H) , 7.15 (d, J=8.7 Hz, 2H), 7.13 (d,J=1.9 Hz, 1H), 7.03 (d, J=1.3 Hz, 1H), 6.93 (d, J=1.3 Hz, 1H) , 5.18(bs, 1H), 4.55-4.42 (m, 2H), 3.92 (s, 3H) , 3.51-3.43 (m, 1H), 3.34-3.27(m, 1H), 2.62-2.53 (m, 1H), 2.31-2.20 (m, 1H), 2.04-1.97 (m, 1H) ,1.71-1.63 (m, 1H), 1.42 (s, 3H), 1.35 (s, 3H), 1.28 (s, 9H), 0.81 (m,2H), 0.04 (s, 9H). MS (IS) m/e: 650 (MH⁺).

EXAMPLE 434-[[[[5,6,7,8-Tetrahydro-5,5-dimethyl-8-[1-(2-trimethylsilanyl-ethoxymethyl)-2-imadazolyl]-8-hydroxyl-2-naphthalenyl]carbonyl]amino]benzoicacid, methyl ester ##STR48##

Using the method given for the preparation of the 8-(4-pyridinyl)derivative XIXb, 560 mg (0.86 mmol) of product from Example 42 gave 473mg (Y: 99%) of the title product. ¹ H NMR (CDCl₃): δ9.23 (bs, 1H),7.95-7.89 (m, 3H), 7.76-7.73 (m, 2H), 7.60-7.57 (m, 2H), 7.47 (bs, 1H),7.23 (d, J=1.9 Hz, 1H), 4.83 (m, 2H), 3.88 (s, 3H), 3.56-3.48 (m, 1H),3.40-3.31 (m, 1H), 2.50-2.38 (m, 2H), 2.27-2.18 (m, 1H), 1.68-1.62 (m,1H), 1.39 (s, 3H), 1.36 (s, 3H), 0.83 (m, 2H), 0.04 (s, 9H). MS (IS)m/e: 550 (MH⁺).

EXAMPLE 444-[[[[5,6,7,8-Tetrahydro-5,5-dimethyl-8-(2-imadazolyl)-8-hydroxy]-2-naphthalenyl]carbonyl]animo]benzoicacid, methyl ester (XIXc) ##STR49##

To a solution of compound made in Example 43 (473 mg, 0.86 mmol) intetrahydrofuran (5 mL) was added tetrabutylammonium fluoride (5.17 mmol,5.17 mL of a 1N solution in tehahydrofuran). After 16 h at reflux thereaction mixture was concentrated in vacuo, diluted with ethyl acetate(50 mL) and washed with water (50 mL×2). The organic phase was thendried through anhydrous sodium sulfate and concentrated in vacuo to give215 mg (Y: 60%) of the title product. ¹ H NMR (CD₃ OD): δ7.82-7.77 (m,2H), 7.64-7.52 (m, 6H), 7.38 (d, J=8.4 Hz, 1H), 3.69 (s, 3H), 2.33-2.28(m, 1H), 1.98-1.90 (m, 1H), 1.82-1.78 (m, 1H), 1.52-1.48 (m, 1H), 1.22(s, 3H), 1.19 (s, 3H). MS (IS) m/e: 420 (MH⁺) .

EXAMPLE 454-[[[[5,6-Dihydro-5,5-dimethyl-8-(2-imadazolyl)]-2-naphthalenyl]carbonyl]amino]benzoicacid, methyl ester (I¹ i) ##STR50##

Using the method given for the preparation of the 8-(3-pyridinyl)derivative I¹ f, 215 mg (0.51 mmol) of compound XIXc gave 94 mg (Y: 46%)of the title product. ¹ H NMR (CD₃ OD): δ7.80-7.75 (m, 3H) , 7.63-7.59(m, 3H), 7.36 (d, J=8.2 Hz, 1H), 6.93-6.92 (m, 2H), 6.25 (t, J=4.5 Hz,1H), 3.68 (3H), 2.24 (d, J=4.5 Hz, 2H), 1.15 (s, 6H). MS (DCI)m/e: 402(MH⁺).

EXAMPLE 464-[[[[5,6-Dihydro-5,5-dimethyl-8-(2-imadazolyl)]-2-naphthalenyl]carbonyl]amino]benzoicacid (I² i) ##STR51##

Using the method given for the preparation of the 8-(2-thienyl)derivative I2a, 94 mg (0.23 mmol) of compound I¹ i gave 49 mg (Y: 54% )of the title product. ¹ H NMR (DMSO): δ14.52 (bs, 1H), 12.72 (bs, 1H),10.56 (s, 1H) , 7.98-7.85 (m, 5H), 7.73 (s, 2H), 7.65 (s, 1H), 7.61 (d,J=8.1 Hz, 1H), 6.77 (t, J=4.5 Hz, 1H), 2.47 (d, J=4.5 Hz, 2H), 1.31 (s,6H). MS (IS) 386 (MH⁻). IR (KBr): 3432, 2962, 1684, 1596. Anal. calcd.for C₂₃ H₂₁ N₃ O₃.1.0 H₂ O .1.0 HCl.0.30 CH₃ CO₂ CH₂ CH₃ :C, 62.06; H,5.68; N, 8.97. Found: C,62.33; H, 5.76; N, 8.60.

EXAMPLE 47N-4-[[[[5,6,7,8-Tetrahydro-5,5-dimethyl-8-(4-isoquinolinyl)-8-hydroxy]-2-naphthalenyl]carbonyl]amino]benzoicacid, methyl ether (XVIIId) ##STR52##

Using the method given for the preparation of the 8-(5-pyrimidinyl)derivative Xc, reaction of compound XVIIb (1.04 g, 2.31 mmol) and4-isoquinolinyl lithium (0.30M solution in THF, 3.5 mmol, 11.6 ml;prepared by treating 4-bromoisoquinoline with n-butyllithium at -78° C.gave 425 mg (Y: 32%) of the title product. ¹ H NMR (CDCl₃): δ9.38 (s,1H), 8.20-8.17 (m, 2H), 7.88-7.85/M, 3H), 7.74-7.70 (m, 3H), 7.63-7.61(m, 2H), 7.04-7.01 (m, 2H), 3.92 (s, 3H), 2.63-2.53 (m, 2H), 2.15-2.07(m, 1H), 1.69-1.53 (m, 1H), 1.50 (s, 3H), 1.31 (s, 3H), 1.22 (s, 9H). MS(IS)m/e: 581 (MH⁺).

EXAMPLE 484-[[[5,6,7,8-Tetrahydro-5,5-dimethyl-8-(4-isoquinolinyl)-8-hydroxy]-2-naphthalenyl]carbonyl]amino]benzoicacid, methyl ester (XIXXd) ##STR53##

Using the method given for the preparation of the 8-(4-pyridinyl)derivative XIXb, 425 mg (0.73 mmol) of compound XVIIId gave 351 mg (Y:99%) of the title product. ¹ H NMR (CDCl₃): δ9.35 (m, 1H), 7.89-7.64 (m,5H), 7.29-7.16 (m, 7H), 3.82 (s, 3H), 2.56-2.42 (m, 2H), 2.12-2.07 (m,1H), 1.75-1.70 (m, 1H), 1.52 (s, 3H), 1.51 (s, 3H). MS (IS)m/e: 481(MH⁺).

EXAMPLE 494-[[[[5,6-Dihydro-5,5-dimethyl-8-(4-isoquinolinyl)]-2-naphthalenyl]carbonyl]amino]benzoicacid, methyl ester (I¹ j) ##STR54##

Using the method given for the preparation of the 8-(3-pyridinyl)derivative I¹ f, 351 mg (0.73 mmol) of compound XIXd gave 280 mg (Y:83%) of the title product. ¹ H NMR (CDCl₃): δ9.31 (s, 1H), 8.47 (s, 1H),8.12 (t, J=4.0 Hz, 1H) , 8.02 (d, J=1.8 Hz, 1H) , 7.92 (d, J=8.8 Hz,2H), 7.79 (dd, J=8.0, 1.9 Hz, 1H), 7.72-7.67 (m, 3H), 7.57 (d, J=8.8 Hz,2H), 7.07 (d, J=1.9 Hz, 1H), 6.22 (dt, J=3.7, 1.6 Hz, 1H), 3.86 (s, 3H),2.54 (m, 2H), 1.52 (s, 3H), 1.47 (s, 3H). MS (DCI) m/e: 463 (MH⁺).

EXAMPLE 504-[[[[5,6-Dihydro5,5-dimethyl-8-(4-isoquinolinyl)]-2-naphthalenyl]carbonyl]amino]benzoicacid (I² j ) ##STR55##

Using the method given for the preparation of the 8-(2-thienyl)derivative I² a, 280 mg (0.61 mmol) of compound I^(i) j gave 240 mg (Y:88%) of the title product. ¹ H NMR (DMSO): δ10.39 (s, 1H), 9.85 (s, 1H),8.64 (s, 1H), 8.54 (d, J=8.0 Hz, 1H), 8.05-7.89 (m, 3H), 7.81 (d, J=8.5Hz, 2H), 7.75 (m, 1H), 7.72 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.0 Hz 1H),6.96 (s, 1H), 6.33 (t, J=4.5 Hz, 1H), 2.53 (d, J=4.5 Hz, 2H), 1.48 (s,3H), 1.42 (s, 3H). MS (DCI) m/e: 449 (MH⁺). IR (KBr): 3420, 2960, 1699,1594, 1524. Anal. calcd. for C₂₉ H₂₄ N₂ O₃.1.0 HCl.1.25 H₂ O: C, 68.63;H, 5.46; N, 5.52. Found: C, 68.63; H, 5.65; N, 5.20.

EXAMPLE 51N-4-[[[[5,6,7,8-Tetrahydro-5,5-dimethyl-8-(3-quinolinyl)-8-hydroxy]-2-naphthalenyl]carbonyl]amino]benzoicacid, methyl ester (XVIIIe) ##STR56##

Using the method given for the preparation of the 8-(5-pyrimidinyl)derivative Xc, reaction of compound XVIIb (865 mg, 1.92 mmol) and3-quinolinyl lithium (0.30M solution in THF, 2.88 mmol, 9.6 ml; preparedby treating 3-bromoquinoline with n-butyllithiym at -78° C.) gave 352 mg(Y: 32%) of the title product. ¹ H NMR (CDCl₃): δ8.8 (d, J=2.2 Hz, 1H),7.97 (d, J=8.7 Hz, 2H), 7.99-7.96 (m, 1H), 7.80-7.69 (m, 3H), 7.58-7.52(m, 3H), 7.16 (d, J=8.7 Hz, 2H), 7.17-7.14 (m, 1H), 3.90 (s, 3H),2.38-2.21 (m, 2H), 1.97-1.88 (m, 1H) , 1.67-1.60 (m, 1H), 1.45 (s, 3H),1.40 (s, 3H), 1.18 (s, 9H). MS (IS) m/e: 581 (MH⁺).

EXAMPLE 524-[[[[5,6,7,8-Tetrahydro-5,5-dimethyl-8-(3-quinolinyl)-8-hydroxy]-2-naphthalenyl]carbonyl]amino]benzoicacid, methyl ester (XIXe) ##STR57##

Using the method given for the preparation of the 8-(4-pyridinyl)derivative XIXb, 350 mg (0.60 mmol) of compound XIXb gave 289 mg (Y:99%) of the title product. ¹ H NMR (CDCl₃): δ9.50 (d, J=1.7 Hz, 1H),9.29 (s, 1H), 8.32-8.29 (m, 3H), 7.98-7.75 (m, 7H), 7.61-7.56 (m, 3H),3.85 (s, 3H), 2.41-2.32 (m, 1H), 2.17-2.08 (m, 1H), 1.99-1.91 (m, 1H),1.58-1.49 (m, 1H), 1.40 (s, 6H). MS (IS)m/e: 481 (MH⁺).

EXAMPLE 534-[[[[5,6-Dihydro-5,5-dimethyl-8-(3-quinolinyl)]-2-naphthalenyl]carbonyl]amino]benzoicacid, methyl ester (I¹ k) ##STR58##

Using the method given for the preparation of the 8-(3-pyridinyl)derivative I¹ f, 289 mg (0.60 mmol) of compound XIXe gave 254 mg (Y:91%) of the title product. ¹ H NMR (CDCl₃): δ8.88 (dd, J=2.0 Hz, 1H),8.18 (dd, J=2.0 Hz, 1H), 8.14 (d, J=8.4 Hz, 1H), 8.03 (d, J=1.1 Hz, 1H),7.94 (d, J=8.8 Hz, 2H), 7.93-7.71 (m, 3H), 7.61 (d, J=8.8 Hz, 2H),7.60-7.26 (m, 3H), 6.22 (t, J=4.5 Hz, 1H), 3.87 (s, 3H), 2.47 (d, J=4.5Hz, 2H) , 1.27 (s, 6H) . MS (IS)m/e: 463 (MH⁺).

EXAMPLE 544-[[[[5,6-Dihydro-5,5-dimethyl-8-(3-quinolinyl)]-2-naphthalenyl]carbonyl]amino]benzoicacid (I² k) ##STR59##

Using the method given for the preparation of the 8-(2-thienyl)derivative I² a, 254 mg (0.55 mmol) of compound I¹ k gave 185 mg (Y:75%) of the title product. ¹ H NMR (DMSO): δ10.44 (s, 1H), 9.18 (d,J=1.8 Hz, 1H), 8.84 (s, 1H), 8.23 (d, J=8.5 Hz, 2H), 7.99 (d, J=7.3 Hz,1H), 7.93 (dd, J=8.1, 1.8 Hz, 1H), 7.86-7.76 (m, H), 7.61 (d, J=8.1 Hz,1H), 7.50 (d, J=1.8 Hz, 1H), 6.41 (t, J=4.5 Hz, 1H), 2.46 (d, J=4.5 Hz,2H), 1.37 (s, 6H). MS (DCI)m/e: 449 (MH⁺). IR (KBr): 3420, 1702, 1656,1594. Anal. calcd. for C₂₉ H₂₄ N₂ O₃.1.5 H₂ O: C, 68.03; H, 5.51; N,5.47. Found: C, 67.71; H, 5.52; N, 5.10.

EXAMPLE 55N-[2-(Trimethylsilyl)ethoxymethyl]-4-[[[[5,6,7,8-tetrahydro-5,5-dimethyl-8-(2-thiazolyl)-8-hydroxyl-2-naphthalenyl]carbonyl]amino]benzoicacid, methyl ester (XVIIIf) ##STR60##

Using the method given for the preparation of the 8-(5-pyrimidinyl)derivative Xc, reaction of compound XVIIa (1.62 g, 3.37 mmol) and2-thiazolyl lithium (0.32M solution in THF, 15.0 ml, 4.8 mmol; preparedby treating 2-bromothiazole with n-butyllithium at -78° C.) gave 497 mg(Y: 26%) of the title product. ¹ H NMR (CDCl₃): δ7.82 (d, J=8.4 Hz, 2H), 7.66 (d, J=3.3 Hz, H), 7.47 (dd, J=8.2 Hz, 1.5 Hz, 1H), 7.32 (d, J=8.2Hz, 1H), 7.20 (d, J=1.5 Hz, 1H), 7.17 (d, J=3.3 Hz, 1H), 7.10 (d, J=8.4Hz, 2H), 5.29 (d, J=10.0 Hz, 1H), 5.14 (d, J=10.0 Hz, 1H), 3.91 (s, 3H),3.72-3.61 (m, 2H), 2.42-2.34 (m, 1H), 2.25-2.14 (m, 1H), 1.88-1.80 (m,1H), 1.73-1.64 (m, 1H), 1.31 (s, 6H), 0.98-0.92 (m, 2H), 0.00 (s, 9H).MS (DCI)m/e: 567 (MH⁺).

EXAMPLE 564-[[[[5,6,7,8-Tetrahydro-5,5-dimethyl-8-(2-thiazolyl)-8-hydroxyl-2-naphthalenyl]carbonyl]amino]benzoicacid, methyl ester (XIXf) ##STR61##

Using the method given for the preparation of the 8-(3-pyridinyl)derivative XIXa, 497 mg (0.88 mmol) of compound XVIIIf gave 126 mg (Y:33%) of the title product. ¹ H NMR (CDCl₃): δ8.05 (d, J=8.5 Hz, 2H),7.88-7.82 (m, 2H), 7.80 (d, J=3.3 Hz, 1H), 7.69 (d, J=8.5 Hz, 2H), 7.54(d, J=8.2 Hz, 1H), 7.33 (d, J=3.3 Hz, 1H), 3.90 (s, 3H), 2.53-2.48 (m,1H), 2.39-2.29 (m, 1H), 2.02-1.92 (m, 1H), 1.88-1.78 (m, 1H), 1.39 (s,6H). MS (DCI)m/e: 437 (MH⁺).

EXAMPLE 574-[[[[5,6-Dihydro-5,5-dimethyl-8-(2-thiazolyl)]-2-naphthalenyl]carbonyl]amino]benzoicacid, methyl ester (I¹ m) ##STR62##

Using the method given for the preparation of the 8-(2-thienyl)derivative I² a, 126 mg (0.29 mmol) of compound XIXf gave 44 mg (Y: 36%)of the title product. ¹ H NMR (CDCl₃): δ8.29 (d, J=1.9 Hz, 1H), 8.17(bs, 1H), 8.04 (d, J=8.8 Hz, 2H), 7.91 (d, J=3.3 Hz, 1H), 7.83 (dd,J=8.1, 1.9 Hz, 1H), 7.73 (d, J=8.8 Hz, 2H) , 7.50 (d, J=8.1 Hz, 1H),7.33 (d, J=3.3 Hz, 1H), 6.65 (t, J=4.5 Hz, 1H), 3.91 (s, 3H), 2.44 (d,J=4.5 Hz, 2H), 1.36 (s, 6H). MS (DCI)m/e: 491 (MH⁺).

EXAMPLE 584-[[[[5,6-Dihydro-5,5-dimethyl-8-(2-thiazolyl)]-2-naphthalenyl]carbonyl]amino]benzoicacid (I² m) ##STR63##

Using the method given for the preparation of the 8-(2-thienyl)derivative I² a, 44 mg (0.10 mmol) of compound I¹ m gave 14 mg (Y: 33%)of the title product. ¹ H NMR (DMSO): δ10.47 (s, 1H), 8.25 (d, J=1.7 Hz,1H), 7.94-7.83 (m, 6H), 7.75 (d, J=3.3 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H),6.67 (t, J=4.5 Hz, 1H), 2.41 (d, J=4.5 Hz, 2H), 1.29 (s, 6H). MS(IS)m/e: 403 (MH⁻). IR (KBr):3432, 1684, 1596, 1528. Anal. calcd. forC₂₃ H₂₀ N₂ O₃ S, . 0.50 H₂ O: C, 61.40; H, 4.93; N, 6.23. Found C,61.64; H, 5.21; N, 5.96.

EXAMPLE 59N-[2-(Trimethylsilyl)ethoxymethyl]-4-[[[[5,6,7,8-tetrahydro-5,5-dimethyl-8-(2-pyridinyl)-8-hydroxyl-2-naphthalenyl]carbonyl]amino]benzoicacid, methyl ester (XVIIIg) ##STR64##

Using the method given for the preparation of the 8-(5-pyrimidinyl)derivative Xc, reaction of compound XVIIa (1.15 g, 2.39 mmol) and2-pyridinyl lithium (0.32M solution in THF, 14.9 ml, 4.8 mmol; preparedby treating 2-bromopyridine with n-butyllithium at -78° C.) gave 470 mg(Y: 35%) of the title product. ¹ H NMR (CDCl₃): δ8.52-8.50 (m, 1H), 7.75(d, J=8.7 Hz, 2H), 7.44-7.41 (m, 2H), 7.32 (d, J=8.4 Hz, 1H), 7.19-7.13(m, 1H), 7.04 (d, J=8.7 Hz, 2H), 6.79 (d, J=1.9 Hz, 1H), 6.48 (d, J=8.0Hz, 1H), 5.29 (d, J=10.0 Hz, 1H), 5.04 (d, J=10.0 Hz, 1H), 3.93 (s, 3H),3.69-3.54 (m, 2H), 2.07-2.03 (m, 2H), 1.95-1.83 (m, 1H), 1.60-1.50 (m,1H), 1.34 (s, 3H), 1.32 (s, 3H), 0.93-0.87 (m, 2H), 0.03 (s, 9H). MS(DCI)m/e: 561 (MH⁺).

EXAMPLE 604-[[[[5,6,7,8-Tetrahydro-5,5-dimethyl-8-(2-pyridinyl)-8-hydroxy]-2-naphthalenyl]carbonyl]amino]benzoicacid, methyl ester (XIXg) ##STR65##

Using the method given for the preparation of the 8-(3-pyridinyl)derivative XIXa, 470 mg (0.84 mmol) of compound XVIIIa gave 208 mg (Y:58%) of the title product. ¹ H NMR (CDCl₃): δ8.62 (dd, J=4.6, 0.9 Hz,1H), 7.99 (d, J=8.7 Hz, 2H), 7.91 (bs, 1H), 7.81 (dd, J=8.4 Hz, 2.1 Hz,1H), 7.66 (d, J=8.7 Hz, 2H), 7.63-7.59 (m, 2H), 7.56 (d, J=8.4 Hz, 1H),7.48 (d, J=2.1 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 3.89 (s, 3H), 2.20-2.15(m, 2H), 2.07-1.92 (m, 1H), 1.72-1.63 (m, 1H), 1.43 (s, 3H), 1.42 (s,3H). MS (DCI)m/e: 431 (MH⁺).

EXAMPLE 614-[[[[5,6-Dihydro-5,5-dimethyl-8-(2-pyridinyl)]-2-naphthalenyl]carbonyl]amino]benzoicacid, methyl ester (I¹ n) ##STR66##

Using the method given for the preparation of the 8-(3-pyridinyl)derivative I¹ f, 208 mg (0.48 mmol) of compound XIXg gave 62 mg (Y: 31%)of the title product. ¹ H NMR (CDCl₃): δ8.72-8.68 (m, 1H) , 8.02 (d,J=8.7 Hz, 2H), 7.81-7.72 (m, 2H), 7.67 (d, J=8.7 Hz, 2H), 7.64 (d,J=1.9Hz, 1H), 7.50 (d, J=8.2 Hz, 1H), 7.46 (m, 1H), 7.32-7.28 (m, 1H),6.38 (t, J=4.5 Hz, 1H), 3.90 (s, 3H), 2.44 (d, J=4.5 Hz, 2H), 1.38 (s,6H). MS (DCI)m/e: 413 (MH⁺).

EXAMPLE 624-[[[[5,6-Dihydro-5,5-dimethyl-8-(2-pyridinl)]-2-naphthalenyl]carbonyl]amino]benzoicacid (I² n) ##STR67##

Using the method given for the preparation of the 8-(2-thienyl)derivative I² a, 62 mg (0.15 mmol) of compound I¹ n gave 47 mg (Y: 78%)of the title product. ¹ H NMR (CDCl₃): δ9.24 (bs, 1H), 8.69 (d, J=4.5Hz, 1H), 7.89(m, 1H), 7.88 (d, J=8.7 Hz, 2H), 7.79 (d, J=8.7 Hz, 2H),7.66 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.49-7.38 (m, 3H), 6.33(t, J=4.5 Hz, 1H), 2.40 (d, J=4.5 Hz, 2H), 1.33 (s, 6H). MS (DCI) m/e:399 (MH⁺). IR (KBr): 3445, 2960, 1680, 1596. Anal. calcd. for C₂₅ H₂₂ N₂O₃. 1.25 H₂ O: C, 71.33; H, 5.87; N, 6.65. Found: C, 71.48; H, 5.95; N,6.24.

EXAMPLE 63 4,4-Dimethyl-7-iodo-1-tetralone (XXIIa)

To a solution of 4,4-dimethyl-7-amino-1-tetralone (XXIa) (1.82 g, 10.0mmol) in concentrated hydrochloric acid (4.69 mL) was added ice coldwater (3.13 mL). The reaction mixture was then cooled to 0° C. by use ofan ice-salt bath. The reaction mixture was then diazotized by thedropwise addition with stirring of a solution of sodium nitrite (0.76 g,11.0 mmol) in water (3.13 mL) keeping temperature between 0°-5° C. Afterstirring for 15 minutes, the reaction mixture was added to a solution ofpotassium iodide (3.63 g, 21.9 mmol) in water (18.8 mL). After standingfor 30 minutes, the dark gum was extracted with ethyl acetate (1×100mL). The organic phase was then concentrated in vacuo and the residuechromatographed on silica gel (eluted with 5% ethyl acetate in hexane)to give 1.56 g (Y: 54%) of the title product. ¹ H-NMR (CDCl₃): δ8.33 (d,J=2.0 Hz, 1H), 7.82 (dd, J=8.3, 2.0 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H),2.72 (t, J=6.8 Hz, 2H), 2.01 (t, J=6.8 Hz, 2H), 1.37 (s, 6H); MS (DCI)m/e: 301 (MH⁺).

EXAMPLE 64 Methyl 4-vinylbenzoate ##STR68##

To a solution of 4-vinylbenzoic acid (Aldrich, 2.18 g, 14.7 mmol) inanhydrous acetonitrile (14.0 mL) was added 1.8-diazabicyclo[5.4.0]undec-7-ene (Aldrich, 2.46 g, 16.2 mmol) and iodomethane(Aldrich, 3.13g, 22.1 mmol) at 0° C. The reaction mixture was thenwarmed to room temperatue and allowed to stir for 3 h. Ethyl acetate(100 mL) was added to the mixture and the solution was washed with brine(50 mL). The organic phase was then separated and concentrated in vacuo.The residue was chromatographed on silica gel (eluted with 5% ethylacetate in hexane) to give 1.05 g (Y: 44%) of the title product. ¹ H-NMR(CDCl₃): δ8.00 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 6.76 (m, 1H),5.87 (d, J=17.6 Hz, 1H), 5.38 (d, J=11.0 Hz, 1H), 3.91 (s, 3H); MS(DCI)m/e: 163 (MH⁺).

EXAMPLE 65 4-[[(E)-(5,6,7,8-Tetrahydro-5,5-dimethyl-8-oxo)-2-naphthalenyl]ethenyl]benzoic acid, methyl ester (XXIIIa) ##STR69##

To a solution of 4,4-dimethyl-7-iodo-1-tetralone (XXIIa) (1.55 g, 5.17mmol) and methyl 4-vinylbenzoate (1.67 g, 10.34 mmol) indimethylformamide (16.0 mL) was added palladium (II) acetate (Aldrich,58 mg, 0.259 mmol), tetrabutylammonium chloride hydrate (Aldrich, 1.49g, 5.17 mmol) and sodium bicarbonate (Mallinckrodt, 1.09 g, 12.9 mmol).The reaction mixture was heated to 70° C. for 4 h and then allowed tostir at room temperature for 16 h. Ethyl acetate (50 mL) was added tothe mixture and the solution was washed with brine (50 mL). The organicphase was concentrated in vacuo and the residue chromatographed onsilica gel (eluted with 10% ethyl acetate in hexane) to give 1.29 g (Y:75%) of the title compound. ¹ H-NMR (CDCl₃): δ8.19 (d, J=1.7 Hz, 1H) ,8.04 (d, J=8.2 Hz, 2H), 6.69 (dd, J=8.1, 1.7 Hz, 1H), 7.57 (d, J=8.2 Hz,2H), 7.45 (d, J=8.1 Hz, 1H), 7.21 (s, 2H), 3.93 (s, 3H), 2.76 (t, J=6.8Hz, 2H), 2.05 (t, J=6.8 Hz, 2H), 1.41 (s, 6H); MS (DCI)m/e: 335 (MH⁺).

EXAMPLE 664-[[(E)-[5,6,7,8-Tetrahydro-5,5-dimethyl-8-(3-pyridinyl)-8-hydroxy]-2-naphthalenyl]ethenyl]benzoicacid, methyl ester (XXIVa) ##STR70##

Using the method for the preparation of the 8-(5-pyrinidinyl) derivativeXc, reaction of compound XXIIIa (1.31g, 3.93 mmol) and 3-pyridinyllithium (0.32M solution in THF, 25.0 ml, 8.0 mmol; prepared by treating3-bromopyridine with n-butyllithium at -78° C.) gave 881 mg (Y: 54%) ofthe title product. ¹ H-NMR (CDCl₃): δ8.55 (d, J=3.1 Hz, 1H), 8.50 (d,J=6.4 Hz, 1H) , 7.97 (d, J=8.1 Hz, 2H) , 7.66 (dd, J=8.0, 1.8 Hz, 1H),7.49-7.42 (m, 4H), 7.26-7.21 (m, 2H), 7.06 (d, J=16.4 Hz, 1H), 6.96 (d,J=16.4 Hz, 1H), 3.91 (s, 3H) , 2.22-2.18 (m, 2H), 1.94-1.85 (m, 1H),1.61-1.53 (m, 1H), 1.40 (s, 3H), 1.36 (s, 3H); MS (DCI)m/e: 414 (MH⁺).

EXAMPLE 674-[[(E)-[5,6-Dihydro-5,5-dimethyl-8-(3-pyridinyl)-2-naphthalenyl]ethenyl]benzoicacid, methyl ester (I³ a) ##STR71##

Using the method for the preparation of the 8-(3-pyridinyl)derivative I¹f, 880 mg (2.13 mmol) of compound I³ a gave 709 mg (Y: 84%) of the titlecompound. ¹ H-NMR (CDCl₃): δ8.66-8.63 (m, 2H), 7.98 (d, J=8.1 Hz, 2H),7.73 (dd, J=8.0, 1.8 Hz, 1H), 7.49 (d, J=8.1 Hz, 2H), 7.45 (d, J=1.8 Hz,1H), 7.41-7.39 (m, 2H), 7.09 (d, J=16.4 Hz, 1H), 7.06 (s, 1H), 6.88 (d,J=16.4 Hz, 1H ), 6.08 (t J=4.5 Hz, 1H ), 3.91 (s, 3H), 2.40 (d, J=4.5Hz,2H), 1.36 (s, 6H); MS (DCI) m/e: 396 (MH⁺).

EXAMPLE 684-[[(E)-[5,6-Dihydro-5-5-dimethyl-8-(3-pyridinyl)-2-naphthalenyl]ethenyl]benzoicacid (I⁴ a) ##STR72##

To a solution of compound I³ a (709 mg, 1.79 mmol) in ethyl alcohol (10ml ) and tetrahydrofuran (3 ml ) was added 10N NaOH (25.0 mmol, 2.50 ml) at 70° C. After 1/4 h, an excess of 1N HCl (50 ml) was added and theprecipatate collected by vacuum filtration. The solid waschromatographed on silica gel (eluted with 10% methyl alcohol inmethylene chloride) to give 560 mg (Y: 82%) of the title product. ¹H-NMR (DMSO): δ8.94-8.92 (m, 2H), 8.53 (d, J=8.1 Hz, 1H), 8.11-8.06 (m,1H), 7.87 (d, J=8.1 Hz, 2H), 7.61 (d, J=1.8 Hz, 2H), 7.60 (m, 1H), 7.45(d, J=8.1 Hz, 1H), 7.30 (d, J=16.4 Hz, 1H), 7.16 (d J=16.4 Hz, 1H), 7.08(s, 1H), 6.32 (t, J=4.5Hz, 1H), 2.38(d, J=4.5Hz, 2H), 1.30 (s, 6H); MS(DCI) m/e: 382 (MH⁺); IR (KBr): 3424, 2956, 1680, 1604 cm⁻¹ ; Anal.calc. for C₂₆ H₂₂ N₁ O₂.1.0 HCl. 1.0 H₂ O: C, 71.80; H, 5.79; N, 3.22.Found: C, 72.12; H, 5.75; N, 3.09.

This invention is further illustrated by the following biological tests,which are illustrative only.

Rhino Mouse Study

Representatives from compounds of formula I were tested for their effecton utriculi reduction on rhino mouse and directly compared to all-transretinoic acid.

Rhino mouse utriculi reduction assay

Six to nine week old female hairless rhino mice (hr^(rh) /hr^(rh)) wereproduced in the Bristol-Myers Squibb colony. Test retinoids in ethanolvehicle (50 ul) were applied to the dorsal area (approximately 1.5×3cm²) of rhino mice once daily for 5 days (Monday to Friday). For variousretinoids, a dose response was obtained with concentrations ranging from0.00033 mM to 16.5 mM. The animals were sacrificed on the followingMonday by CO₂ inhalation. A 7/8" full thickness punch was taken from thecentral dorsal area of each animal. The epidermis of the biopsy wasremoved from the dermis after incubation in 0.5% acetic acid overnightat 4° C. The separated epidermis was then fixed in formalin, dehydratedwith ethanol, and cleared in xylene. To determine the utriculi diameter,each epidermis sheet was placed on a glass slide in xylene. For eachspecimen, the diameter of 40 utricules was measured with an imageanalysis system (IBM PC, Image Measure program and Olympus microscopewith video camera). % Utriculi reduction was calculated as ##EQU1##

Since the maximum effect in this assay is approximately 60% utriculireduction, the activity of various test compounds is reported as ED₃₀ inTable 1, the concentration to reach 30% (half-maximum) utriculireduction.

                  TABLE 1                                                         ______________________________________                                        Compound*      ED.sub.30 (mM)                                                 ______________________________________                                        I.sup.2 e      3.89                                                           I.sup.2 a      >10                                                            I.sup.2 g      2.07                                                           ______________________________________                                         *Compounds I.sup.2 f and I.sup.2 d were also tested, but found to be          inactive in this model.                                                  

The following biological test indicates that the compounds of theinstant invention possess cytotoxicity activity normally associated withretinoids. Thus in one aspect, the invention provides a method oftreating various tumors.

Cytotoxicity Result

The cytotoxicity assay was set up similar to those run by the NationalCancer Institute (D. A. Scudiero, et al, "Evaluation of a SolubleTetrazolium/Formazan Assay for Cell Growth and Drug Sensitivity inCulture Using Human and Other Tumor Cell Lines", Cancer Research, 48,4827-4833, Sep. 1, 1988; M. C. Alley, et al, "Feasibility of DrugScreening with Panels of Human Tumor Cell Lines Using a MicrocultureTetrazolium Assay", Cancer Research, 48, 589-601, Feb. 1, 1988) with theexception that the new vital stain alamarBLue™ was used to determinecellular viability. Briefly, the assayed involved plating 1000 cells perwell in a volume of 120 μL in a 96 well flat-bottom dish (Corning) onday -1. Twenty-four hours later the appropriate dilution of a compoundof formula I was added in a volume of 30 μL complete medium (finalvolume 150 μL). The plates were sealed with a plate sealer (DynatechLabs) to prevent evaporation. On day 5 the mylar film was removed and 15μL of sterile alamarBlue was added to each well and the cells wereincubated 37° C. 5% CO₂ for two hours. Using a Vmax plate reader theoptical density for each well was determined having the OD₅₇₀ subtractedfrom the OD₆₀₀. The 100% signal was determined for cells grown incomplete medium containing only 0.5% DMSO. All wells were set-up intriplicate and the mean values were plotted in FIG. 1. The IC₅₀ valueswere determined for the second experiment and are listed in table 2.

                  TABLE 2                                                         ______________________________________                                        IC.sub.50 values for L2987 experiment 2                                       Compound          IC.sub.50 (μM)                                           ______________________________________                                        All trans retinoic acid                                                                         68                                                          I.sup.2 a         64                                                          I.sup.2 b         50                                                          ______________________________________                                    

The compounds of formula I may be used topically or systemically, asanticancer agents and in the treatment, amelioration, or prevention ofthe skin disorders and rheumatic illnesses for which retinoic acid andother retinoids are useful. In this regard, they may be used for therapyin animals, including humans, of premalignant epithelial cell lesions,as a prophylaxis against tumor promotion in epithelial cells andtreatment for dermatoses such as ichthyoses, follicular disorders,benign epithelial disorders, and other proliferative skin diseases(nonmalignant conditions of the skin that are characterized by epidermalcell proliferation or incomplete cell differentiation) such as acne,psoriasis, eczema, atopic dermatitis, nonspecific dermatitis and thelike. The compounds of formula I may also be used in reversing andpreventing the effects of irradiation damage to skin. When used for theabove treatments they will usually be formulated with a pharmaceuticallyacceptable liquid, semi-solid, or solid carrier. A pharmaceuticallyacceptable carrier is a material that is nontoxic and generally inertand does not affect the functionality of the active ingredientsadversely. Such materials are well known and include those materialssometimes referred to as diluents or vehicles (excipients) in thepharmaceutical formulation art. The carrier may be organic or inorganicin nature. Examples of pharmaceutically acceptable carriers that may beused to formulate a compound of formula I are water, gelatin, lactose,starch, mineral oil, cocoa butter, dextrose, sucrose, sorbitol,mannitol, gum acacia, alginates, cellulose, talc, magnesium stearate,polyoxyethylene sorbitan monolaurate, and other commonly usedpharmaceutical carriers. In addition to a compound of formula I andcarrier, the formulation may contain minor amounts of additives such asflavoring agents, coloring agents, thickening or gelling agents,emulsifiers, wetting agents, buffers, stabilizers, and preservativessuch as antioxidants.

The dosages and dosage regimen in which the compounds of formula I areadministered will vary according to the dosage form, mode ofadministration, the condition being treated and particulars of thepatient being treated. Accordingly, optimal therapeutic concentrationswill be best determined at the time and place through routineexperimentation.

In the treatment of dermatoses, it will generally be preferred toadminister the drug topically, though in certain cases such as treatmentof severe cystic acne, oral administration may also be used. If thecompounds according to the invention are used topically, it will befound that they exhibit a good activity over a very broad range ofdilution; in particular, concentrations of the active compound orcompounds ranging from 0.0005% to 2% by weight can generally be used. Itis of course possible to use higher concentrations if this should becomenecessary for a particular application; however, the preferredconcentration of active principle are from 0.002% to 1% by weight.

For topical administration the compounds of formula I are convenientlyprovided in the form of unguents, gels, creams, ointments, powders,dyeing compositions, solutions, suspensions, emulsions, lotions, sprays,adhesive plasters and impregnated pads. The compounds according to theinvention can be mixed with inert nontoxic, generally liquid or pasty,bases suitable for topical treatment. Preparation of such topicalformulations are well described in the art of pharmaceuticalformulations as exemplified, for example, Remington's PharmaceuticalScience, Edition 17, Mack Publishing Company, Easton, Pa. Othermedicaments can be added to such topical formulation for such secondarypurposes as treating skin dryness, providing protection against light;other medications for treating dermatoses, preventing infection,reducing irritation, inflammation and the like.

The compounds according to the invention can also be used enterally.Orally, the compounds according to the invention are suitablyadministered at the rate of 2 μg to 2 mg per day per kg of body weight.The required dose can be administered in one or more portions. For oraladministration, suitable forms are, for example, tablets, pills,dragees, syrups, suspensions, emulsions, solutions, powders andgranules; a preferred method of administration consists in using pillscontaining from 0.1 mg to about 1 mg of active substance.

U.S. Pat. No.4,876,381 issued on Oct. 24, 1989 to Langet al. providesexamples of formulations constituting gel, unguent, powder, cream, etc.for a retinoid compound. The aforesaid U.S. Patent can be used as aguide to formulate a compound of formula I and is herein incorporatedbyreference in its entirety.

Isotretinoin (Accutane®) and etretinate (Tegison®) are used clinicallyto treat severe recalcitrant cystic acne and severe recalcitrantpsoriasis, including the erythrodermica and generalized pustular types,respectively. Their mode of use is amply illustrated in the Physician'sDesk Reference, 47th Edition, 1993, published by Medical Economics Data.The compounds of formula I may also be used to treat severe recalcitrantcystic acne or severe recalcitrant psoriasis. In so doing, the compoundsof the present invention may be used in a similar fashion toisotretinoin and etretinate; thus, the relevant sections on isotretinoinand etretinate in the Physician's Desk Reference will serve as aconvenient guide which will obviate the need for any undueexperimentation.

The compounds according to the invention can also be administeredparenterally in the form of solutions or suspensions for intravenous orintramuscular perfusions or injections. In that case, the compoundsaccording to the invention are generally administered at the rate ofabout 2 μg to 2 mg per day per kg of body weight; a preferred method ofadministration consists of using solutions or suspensions containingapproximately from 0.01 mg to 1 mg of active substance per ml.

Several retinoids have been found to possess anti-tumor properties.Roberts, A. B. and Sporn, M. B. in "The Retinoids," Sporn, M. B.,Roberts, A. B., and Goodman, D. S., eds, 1984, 2 pp. 209-286, AcademicPress, New York; Lippman, S. M., Kessler, J. F., and Meyskens, F. L.,Cancer Treat. Rep., 1987, 71, p. 391; ibid., p. 493. As used herein, theterm "anti-tumor" includes both chemopreventative (prophylactic or tumorpromotion inhibiting) and therapeutic (curative) use. For example,all-trans retinoic acid can be used to treat acute promyelocyticleukemia. Huang, M. et al., Blood, 1988, 72, p. 567. Isotretinoin hasbeen shown to be useful in prevention of second primary tumors insquamous-cell carcinoma of the head and neck. Hong, W. K. et al., N.Engl. J. Med., 1990, 323, p. 795.

The compounds of formula I can also be used in substantially the similarmanner to retinoids for treating (both chemopreventively andtherapeutically) various tumors. For the compounds of this invention,the anti-tumor dose to be administered, whether a single dose, multipledose, or a daily dose, will of course vary with the particular compoundemployed because of the varying potency of the compound, the chosenroute of administration, the size of the recipient, the type of tumor,and the nature of the patient's condition. The dosage to be administeredis not subject to definite bounds, but it will usually be an effectiveamount, or the equivalent on a molar basis of the pharmacologicallyactive free form produced from a dosage formulation upon the metabolicrelease of the active drug to achieve its desired pharmacological andphysiological effects. An oncologist skilled in the art of cancertreatment will be able to ascertain, without undue experimentation,appropriate protocols for the effective administration of the compoundsof this present invention, such as by referring to the earlier publishedstudies on retinoids found to have anti-tumor properties. For example,for the prevention of second primary tumors with a compound of formula Iin squamous-cell carcinoma of the head and neck, an oncologist may referto the study by Hong, W. K. et al. in N. Engl. J. Med., 1990, 323, p.795. For treating acute promyelocytic leukemia, s/he may refer to thestudy by Huang, M. et al. in Blood, 1988, 72, p. 567.

What we claim is:
 1. A compound of formula I ##STR73## in which T is--CONH-- or --CH═CH--;R^(a) and R^(b) are independently C₁₋₆ alkyl;R^(c) is C₁₋₆ alkyl or hydrogen; and R is thienyl, methylthienyl, orfuryl.
 2. A compound of claim 1 in which R is of the formula ##STR74##3. The compound of claim 2 that is4-[[[[5,6-dihydro-5,5-dimethyl-8-(2-thienyl)]-2-naphthalenyl]carbonyl]amino]benzoicacid.
 4. The compound of claim 2 that is4-[[[5,6-dihydro-5,5-dimethyl-8-[2-(3-methylthienyl)]-2-naphthalenyl]carbonyl]amino]benzoicacid.
 5. The compound of claim 2 that is4-[[[[5,6-dihydro-5,5-dimethyl-8-(3-thienyl)]-2-naphthalenyl]carbonyl]amino]benzoicacid.